Translational failure of anti-inflammatory compounds for myocardial infarction: a meta-analysis of large animal models

van Hout GPJ, Jansen of Lorkeers SJ, Wever KE, et al.
Cardiovasc Res 2016 109: 240-248

Background

As a consequence of adverse remodelling, acute myocardial infarction (MI) may progress to chronic heart failure. Remodelling involves infarct expansion, myocardial scar thinning and left ventricular geometrical adaptation [1] and appears to stem from an exaggerated inflammatory response initiated during ischaemia and early reperfusion [2,3].
Inflammatory cells are attracted to damaged tissue. Factors released by the cells clear necrotic cells, which paves the way for scar formation [4]. The inflammatory process is important for stabilisation of scar tissue [5], but its acute effects cause infarct expansion and cardiac function worsening early after ischaemia in the reperfusion phase [6-8].
Based on observations in clinical studies, attenuating the inflammatory response has been hypothesised to be a promising strategy to limit infarct size and preserve cardiac function post-MI. Anti-inflammatory strategies have been shown to have efficacy in reducing reperfusion damage and post-MI remodelling in larger animal models [9], since these more closely resemble human anatomy, haemodynamics and pharmacodynamics.
None of these findings has been reproduced in clinical trials [10,11]. The more complex situation of humans, including presence of comorbidities and behaviour like smoking, as compared with large animal models, may yield a different post-MI inflammatory response. But a possible publication bias and experimental set-up of animal studies may also be relevant.
This study aimed to better understand the translational failure of anti-inflammatory compounds for MI. A meta-analysis was conducted to assess the overall effect of anti-inflammatory compounds in large MI studies, and methodological factors that influenced the outcome were identified by meta-regression. 183 publications were included that reported data on the primary outcome infarct size as percentage of area at risk (IS/AAR) from 3331 animals.

Main results

• Anti-inflammatory treatment gave a mean reduction of IS/AAR of 12.7% (95%CI: 11.1-14.4%, P<0.001). Substantial heterogeneity between studies was seen and there was evidence for a publication bias of small studies.
• After anti-inflammatory treatment, a smaller mean infarct size as percentage of the left ventricle (IS/LV) was seen (difference: 3.9%, 95%CI: 3.1-4.7%, P<0.001), as well as a higher ejection fraction (3.4, 95%CI: 0.8-6.1, P<0.001), as compared with controls. No difference in mortality was observed (OR: 0.96, 95%CI: 0.79-1.17, P=1.0).
• Possible sources of heterogeneity identified with meta-regressions were:
  • Drug class, as a predictor of efficacy for IS/AAR and IS/LV, but not mortality. Leukotriene inhibitors and cell adhesion molecules inhibitors performed best.
  • Time point of outcome measurement, with less apparent effect of treatment at later times of assessment
  • Sex of the animals: for both IS/AAR and IS/LV greater effects were seen in male animals, than in female or mixed populations.
  • Temporary occlusion models showed larger effects on IS/LF than permanent occlusion models.

Conclusion

These data from over 180 studies in large animals confirm that treatment with anti-inflammatory compounds reduce infarct size in these animals. The effect on infarct size appears to depend on the inflammatory pathway that is targeted, since leukotriene inhibitors were more effective than NSAIDs or immunosuppressive drugs. A difference in cardiac tissue after MI between patients and large animal models could lie in the role of inflammatory cells, which might be more important in patients. It might be better to ‘fine-tune’ rather than completely abolish the inflammatory response in patients and also optimal timing of therapy may be different between species.
The study also identified methodological aspects that were predictors of effect size. These should be taken into account to chose clinically relevant animal models to increase the translational value of preclinical research.

Editorial comment [12]

The authors call the above paper a “welcome reminder that, before moving into the clinical arena, we should carefully assess whether the experimental data available are sufficiently convincing and solid to allow a reasonable possibility of success in patients.” They also highlight that an important difference between patients and animal models may be that patients show large variability with regard to many aspects, while in animal models researchers try to obtain a reproducible site of coronary occlusion and duration of ischaemia. Also, experiments are typically performed in healthy young animals, while most patients with acute coronary syndromes are older and they may have a range of comorbidities and possibly under chronic drug treatment.
“The ESC Working Group ‘Cellular Biology of the Heart’, aimed at improving pre-clinical assessment
of cardioprotective therapies called for multicentric randomized animal studies, as it is done in the context of clinical trials, to obtain more robust data.” In addition, the authors propose “it would seem wise to move away from the ‘cleanest’ possible experimental model, and start investigating new therapies under conditions that are more akin to the common clinical scenario.”

Find this article online at Cardiovasc Res

Referenties

1. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981–2988.
2. Timmers L, Pasterkamp G, de Hoog VC, et al. The innate immune response in reperfused myocardium. Cardiovasc Res 2012;94:276–283.
3. Arslan F, de Kleijn DP, Pasterkamp G. Innate immune signaling in cardiac ischemia. Nat Rev Cardiol 2011;8:292–300.
4. Christia P, Frangogiannis NG. Targeting inflammatory pathways in myocardial infarction. Eur J Clin Invest 2013;43:986–995.
5. Timmers L, Sluijter JPG, Verlaan CWJ, et al. Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling,
and impairs systolic function after myocardial infarction in the pig. Circulation 2007;115: 326–332.
6. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004;61:481–497.
7. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res 2002;53:31–47.
8. Arslan F, Smeets MB, O’Neill LA, et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody. Circulation 2010;121:80–90.
9. Libby P, Maroko PR, Bloor CM, et al. Reduction of experimental myocardial infarct size by corticosteroid administration. J Clin Invest 1973;52:599–607.
10. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357: 1121–1135.
11. Seropian IM, Toldo S, van Tassell BW, Abbate A. Anti-inflammatory strategies for ventricular remodeling following St-segment elevation acute myocardial infarction. J Am Coll Cardiol 2014;63:1593–1603.
12. Tritto I, Ambrosio G. Why does pre-clinical success in cardioprotection fail at the bedside? Cardiovasc Res (2016) 109 (2): 189-190